Wound healing agents, including antibiotics for preventing microbe-induced secondary infection, have evolved over the course of a long history, and now a variety of wound healing agents are being developed and used. Since the discovery of penicillin by Fleming in the twentieth century, the development of antibiotics has made great advances. In the beginning, wound healing agents comprised antibiotics alone, but recently these have been used in combination with a protein agent for promoting the regeneration of injured cells, such as EGF (epidermal growth factor), a cytokine, interleukins, or TGF-β (transforming growth factor-beta) to elevate wound healing potentials. However, the emergence of bacteria resistant to pre-existing antibiotics has necessitated the continued development of novel antibiotics.
So long as chemicals with antibiotic activity are employed against bacterial infections, resistance of bacteria to antibiotics is now regarded as inevitable. Hence, what is important for the development of novel antibiotics is not to make bacteria no longer resistant to antibiotics, but to reduce the occurrence and spread of antibiotic resistance.
In an attempt to search for efficient solutions to infections with antibiotic-resistant bacteria, many researchers have paid intensive attention to a new concept of antibiotics. On the other hand, most protein additives are not widely used in wound healing agents because they are very expensive and unstable. Steroids that are found in most of the currently available wound healing agents have the side effect of causing dermatitis. Given this background, antimicrobial peptides are arising as promising alternatives because they show excellent wound healing activity and have almost no side effects on the skin. Many attempts have been made to employ naturally occurring antimicrobial peptides themselves or synthetic analogs thereof. Their practical applications are, however, imparted with lots of limitations because their antimicrobial activity is accompanied by erythrocytolysis. Therefore, extensive studies are being concentrated on the development of peptides that show high antimicrobial activity without cytotoxicity.
Antimicrobial peptides are widely distributed in nature and generally are as short as 5-50 amino acid residues in length. They are almost free of influence by acid, alkali and heat, and can be readily degraded after performing their antimicrobial activity. Among them, cathelicidin LL-37 and magainin2, a magainin derivative, function as potent antibiotics as well as having the ability to regenerate cells. Their ability to regenerate cells starts with the association of the peptides with EGFR (epidermal growth factor receptor) to which EGF (epidermal growth factor), responsible for cell regeneration, binds. It is also found that antimicrobial peptides having alpha-helix structures, like LL-37, can regenerate cells (TokuMaru S. et al., J Immunol. Japan, 175(7), p 4662-4668, 2005).
The use of the antimicrobial peptides in wound healing is being studied by various research groups. For example, human cathelicidin LL-37, ceragenin, cecropin, bacteriocin, fungal defensin and plectasin are in pre-clinical trials for use as wound healing agents, while pexiganan (MSI-78), a derivative of frog magainin, and iseganan (IB-367), a derivative of pig protegrin, are in phase 3 clinical trials for treatment of diabetic foot ulcer and oral mucositis. However, their in-vivo instability, which results in a decrease in wound healing potential, must be negated before they can be used as wound healing agents.
Leading to the present invention, intensive and thorough research into antimicrobial peptides having structural stability and high antimicrobial activity under the physiological conditions, conducted by the present inventors, resulted in the finding that some of the antimicrobial peptides, which were previously developed by the present inventors (Korean Patent No. 10-0836596) to retain high antimicrobial activity even at as high a salt concentration as under physiological conditions, exhibited the activity of promoting the migration and regeneration of skin cells and thus reducing the period of time required for wound healing in vitro and in vivo.